V599EB-RAF is an oncogene in melanocytes
V599EB-RAF is an oncogene in melanocytes
复制标题
DOI：
10.1158/0008-5472.can-03-3433
复制
发表时间：
2004-04-01
期刊：
影响因子：
11.2
通讯作者：
Marais, R
中科院分区：
文献类型：
--
作者：
Wellbrock, C;Ogilvie, L;Marais, R
B-RAF的致癌版本，B-V599E-RAF，在大约70%的人类黑色素瘤中被发现。然而，这种致癌基因在黑色素瘤中的作用尚不清楚，因为B-V559E-RAF也存在于大约80%的良性痣中。我们通过在培养的黑色素细胞中表达B-V599E-RAF，研究了致癌的B-RAF在黑色素瘤早期阶段的作用。在这些细胞中，B-V599E-RAF诱导了组成型丝裂原激活的ERK活化激酶（MEK）和细胞外信号调节激酶（ERK）信号传导、12- o - tetradecanoylphorbol13 -acetate非依赖性生长和裸鼠的致瘤性。有趣的是，在ras转化的黑素细胞中，B-RAF缺失并没有阻断MEK-ERK信号传导或细胞周期进程。同样，B-RAF的缺失阻断了含有致癌B-RAF的人类黑色素瘤细胞中的MEK-ERK信号传导，但在含有致癌RAS的黑色素瘤细胞中没有。因此，尽管B-RAF可以通过MEK和ERK信号传导在黑色素瘤的早期阶段作为一种有效的致癌基因，但由于该通路内的先天冗余，在ras转化的黑色素细胞中不需要这种信号传导。这些发现对未来的治疗策略具有重要意义。
The oncogenic version of B-RAF, B-V599E-RAF, is found in approximately 70% of human melanomas. However, the role that this oncogene plays in melanoma is unclear because B-V559E-RAF is also found in approximately 80% of benign nevi. We have examined the role of oncogenic B-RAF in the early stages of melanoma by expressing B-V599E-RAF in cultured melanocytes. In these cells, B-V599E-RAF induced constitutive mitogen activated ERK-activating kinase (MEK) and extracellular signal-regulated kinase (ERK) signaling, 12-O-tetradecanoylphorbol-13-acetate-independent growth, and tumorigenicity in nude mice. Intriguingly, in RAS-transformed melanocytes, B-RAF depletion did not block MEK-ERK signaling or cell cycle progression. Similarly, B-RAF depletion blocked MEK-ERK signaling in human melanoma cells harboring oncogenic B-RAF, but not in melanoma cells harboring oncogenic RAS. Thus, although B-RAF can act as a potent oncogene in the early stages of melanoma by signaling through MEK and ERK, it is not required for this signaling in RAS-transformed melanocytes due to innate redundancy within the pathway. These findings have important implications for future therapeutic strategies.